Date of Award
10-14-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Antimicrobial resistance is a growing global health crisis, with enzymatic inactivation being particularly concerning, as it can diminish the efficacy of antibiotics across an entire infection environment. This dissertation focuses on tetracycline antibiotics and the emerging class of tetracycline destructases (TDases), which are following a similar evolutionary path as beta-lactamase enzymes. Our research explored various strategies to counteract this resistance, including the design and evaluation of TDase inhibitors derived from anhydrotetracycline. We developed two series of inhibitors: C9-anhydrotetracycline derivatives, which effectively block both tetracycline and NADPH binding, and C10-anhydrotetracyclne derivatives, which improved water solubility and whole-cell activity against multiple bacterial species. Additionally, we pioneered a new approach to combat antibiotic enzymatic inactivation using targeted protein degradation of TetX in Mycobacteria. Through comprehensive analysis of TDase activity, structure, inhibition, and degradation, this work provides a framework for restoring the potency of tetracyclines against resistant bacterial strains.
Language
English (en)
Chair and Committee
Timothy Wencewicz
Committee Members
Christina Stallings; Gautam Dantas; John-Stephen Taylor; Kevin Moeller
Recommended Citation
Williford, Emily, "Bivalent Agents for Inhibiting and Degrading Tetracycline Destructase Enzymes" (2024). Arts & Sciences Electronic Theses and Dissertations. 3268.
https://openscholarship.wustl.edu/art_sci_etds/3268